Short-chain fatty acid butyrate, a breast milk metabolite, enhances immature intestinal barrier function genes in response to inflammation in vitro and in vivo.

Infants born under 1,500 g have an increased incidence of necrotizing enterocolitis in the ileum and the colon, which is a life-threatening intestinal necrosis. This is in part due to excessive inflammation in the immature intestine to colonizing bacteria because of an immature innate immune response. Breastmilk complex carbohydrates create metabolites of colonizing bacteria in the form of short-chain fatty acids (SCFAs). We studied the effect of breastmilk metabolites, SCFAs, on immature intestine with regard to anti-inflammatory effects. This showed that acetate, propionate, and butyrate were all anti-inflammatory to an IL-1ß inflammatory stimulus. In this study, to further define the mechanism of anti-inflammation, we created transcription profiles of RNA from immature human enterocytes after exposure to butyrate with and without an IL-1ß inflammatory stimulus. We demonstrated that butyrate stimulates an increase in tight-junction and mucus genes and if we inhibit these genes, the anti-inflammatory effect is partially lost. SCFAs, products of microbial metabolism of complex carbohydrates of breastmilk oligosaccharides, have been found with this study to induce an anti-IL-1ß response that is associated with an upregulation of tight junctions and mucus genes in epithelial cells (H4 cells). These studies suggest that breastmilk in conjunction with probiotics can reduce excessive inflammation with metabolites that are anti-inflammatory and stimulate an increase in the mucosal barrier.NEW & NOTEWORTHY This study extends previous observations to define the anti-inflammatory properties of butyrate, a short-chain fatty acid produced by the metabolism of breastmilk oligosaccharides by colonizing bacteria. Using transcription profiling of immature enterocyte genes, after exposure to butyrate and an IL-1ß stimulus, we showed that tight-junction genes and mucus genes were increased, which contributed to the anti-inflammatory effect.

Indole-3-lactic acid, a metabolite of tryptophan, secreted by Bifidobacterium longum subspecies infantis is anti-inflammatory in the immature intestine.

BACKGROUND: Necrotizing enterocolitis (NEC), a necrotic inflammation of the intestine, represents a major health problem in the very premature infant. Although prevention is difficult, the combination of ingestion of maternal-expressed breastmilk in conjunction with a probiotic provides the best protection. In this study, we establish a mechanism for breastmilk/probiotic protection. METHODS: Ultra-high-performance liquid chromatography-tandem mass spectrometry of Bifidobacterium longum subsp. infantis (B. infantis) secretions was used to identify an anti-inflammatory molecule. Indole-3-lactic acid (ILA) was then tested in an established human immature small intestinal cell line, necrotizing colitis enterocytes, and other immature human enteroids for anti-inflammatory effects and to establish developmental function. ILA was also examined in immature and mature enterocytes. RESULTS: We have identified ILA, a metabolite of breastmilk tryptophan, as the anti-inflammatory molecule. This molecule is developmentally functional in immature but not mature intestinal enterocytes; ILA reduces the interleukin-8 (IL-8) response after IL-1ß stimulus. It interacts with the transcription factor aryl hydrocarbon receptor (AHR) and prevents transcription of the inflammatory cytokine IL-8. CONCLUSIONS: This molecule produced by B. infantis (ATCC No. 15697) interaction with ingested breastmilk functions in a complementary manner and could become useful in the treatment of all at-risk premature infants for NEC if safety and clinical studies are performed.

Energy Efficiency of Electro-Driven Brackish Water Desalination: Electrodialysis Significantly Outperforms Membrane Capacitive Deionization.

Electro-driven technologies are viewed as a potential alternative to the current state-of-the-art technology, reverse osmosis, for the desalination of brackish waters. Capacitive deionization (CDI), based on the principle of electrosorption, has been intensively researched under the premise of being energy efficient. However, electrodialysis (ED), despite being a more mature electro-driven technology, has yet to be extensively compared to CDI in terms of energetic performance. In this study, we utilize Nernst-Planck based models for continuous flow ED and constant-current membrane capacitive deionization (MCDI) to systematically evaluate the energy consumption of the two processes. By ensuring equivalently sized ED and MCDI systems-in addition to using the same feed salinity, salt removal, water recovery, and productivity across the two technologies-energy consumption is appropriately compared. We find that ED consumes less energy (has higher energy efficiency) than MCDI for all investigated conditions. Notably, our results indicate that the performance gap between ED and MCDI is substantial for typical brackish water desalination conditions (e.g., 3 g L-1 feed salinity, 0.5 g L-1 product water, 80% water recovery, and 15 L m-2 h-1 productivity), with the energy efficiency of ED often exceeding 30% and being nearly an order of magnitude greater than MCDI. We provide further insights into the inherent limitations of each technology by comparing their respective components of energy consumption, and explain why MCDI is unable to attain the performance of ED, even with ideal and optimized operation.

Scaling Resistance in Nanophotonics-Enabled Solar Membrane Distillation.

This study compares the scaling behavior of membrane distillation (MD) with that of nanophotonics-enabled solar membrane distillation (NESMD). Previous research has shown that NESMD, due to its localized surface heating driven by photothermal membrane coatings, is an energy-efficient system for off-grid desalination; however, concerns remained regarding the scaling behavior of self-heating surfaces. In this work, bench-scale experiments were performed, using model brackish water, to compare the scaling propensity of NESMD with MD. The results showed NESMD to be highly resistant to scaling; a three times higher salt concentration factor (c/c0) was achieved in NESMD compared to MD without any decline in flux. Analyses of the scaling layer on NESMD membranes revealed that salt deposition was 1/4 of that observed for MD. Scaling resistance in NESMD is attributed to its lower operating temperature, which increases the solubility of common scalants and decreases salt precipitation rates. Precipitation kinetics measurements revealed an order of magnitude faster precipitation under heated conditions (62 °C, k = 8.7 × 10-2 s-1) compared to ambient temperature (22 °C, k = 7.1 × 10-3 s-1). These results demonstrate a distinct advantage of NESMD over MD for the treatment of high scaling potential water, where scaling is a barrier to high water recovery.

The developmentally regulated fetal enterocyte gene, ZP4, mediates anti-inflammation by the symbiotic bacterial surface factor polysaccharide A on Bacteroides fragilis.

Initial colonizing bacteria play a critical role in completing the development of the immune system in the gastrointestinal tract of infants. Yet, the interaction of colonizing bacterial organisms with the developing human intestine favors inflammation over immune homeostasis. This characteristic of bacterial-intestinal interaction partially contributes to the pathogenesis of necrotizing enterocolitis (NEC), a devastating premature infant intestinal inflammatory disease. However, paradoxically some unique pioneer bacteria (initial colonizing species) have been shown to have a beneficial effect on the homeostasis of the immature intestine and the prevention of inflammation. We have reported that one such pioneer bacterium, Bacteroides fragilis (B. fragilis), and its surface component polysaccharide A (PSA) inhibit IL-1ß-induced inflammation in a human primary fetal small intestinal cell line (H4 cells). In this study, using transcription profiling of H4 cellular RNA after pretreatment with or without PSA before an inflammatory stimulation of IL-1ß, we have begun to further determine the cellular mechanism for anti-inflammation. We show that a developmentally regulated gene, zona pellucida protein 4 (ZP4), is uniquely elevated after IL-1ß stimulation and reduced with PSA exposure. ZP4 was known as a sperm receptor-mediating species-specific binding protein in the initial life of mammals. However, its intestinal epithelial function is unclear. We found that ZP4 is a developmentally regulated gene involved with immune function and regulated by both Toll-like receptor 2 and 4. Knockdown of ZP4-affected PSA inhibited IL-8 mRNA expression in response to IL-1ß. This represents an initial study of ZP4 innate immune function in immature enterocytes. This study may lead to new opportunity for efficient treatment of NEC.NEW & NOTEWORTHY This study extends previous observations to define the cellular mechanisms of polysaccharide A-induced anti-inflammation in immature enterocytes using transcription profiling of enterocyte genes after preexposure to polysaccharide A before an inflammatory stimulus with IL-1ß.

Bronchiolitis obliterans as a long-term sequela of Stevens-Johnson syndrome and toxic epidermal necrolysis in children.

Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are characterized by widespread skin and mucosal blistering and necrosis. The triggers and long-term sequelae in children may differ from those reported for adults. Bronchiolitis obliterans (BO) is an uncommon complication, with only 15 previously reported cases, but can lead to significant long-term morbidity, requiring lung transplantation in some cases. We report three children with nondrug-related SJS (n = 1) and TEN (n = 2) who developed BO. Two were treated with intravenous immunoglobulin therapy (2-2.4 g/kg) and all three survived. We highlight salient learning points from our cases and potential pitfalls in diagnosis of BO, including delayed onset, and we also review the literature.

A prediction model of military combat and training exposures on VA service-connected disability: a CENC study.

Background: Research has shown that number of and blast-related Traumatic Brain Injuries (TBI) are associated with higher levels of service-connected disability (SCD) among US veterans. This study builds and tests a prediction model of SCD based on combat and training exposures experienced during active military service.Methods: Based on 492 US service member and veteran data collected at four Department of Veterans Affairs (VA) sites, traditional and Machine Learning algorithms were used to identify a best set of predictors and model type for predicting %SCD ≥50, the cut-point that allows for veteran access to 0% co-pay for VA health-care services.Results: The final model of predicting %SCD ≥50 in veterans revealed that the best blast/injury exposure-related predictors while deployed or non-deployed were: 1) number of controlled detonations experienced, 2) total number of blast exposures (including controlled and uncontrolled), and 3) the total number of uncontrolled blast and impact exposures.Conclusions and Relevance: We found that the highest blast/injury exposure predictor of %SCD ≥50 was number of controlled detonations, followed by total blasts, controlled or uncontrolled, and occurring in deployment or non-deployment settings. Further research confirming repetitive controlled blast exposure as a mechanism of chronic brain insult should be considered.

Aqueous-Processed, High-Capacity Electrodes for Membrane Capacitive Deionization.

Membrane capacitive deionization (MCDI) is a low-cost technology for desalination. Typically, MCDI electrodes are fabricated using a slurry of nanoparticles in an organic solvent along with polyvinylidene fluoride (PVDF) polymeric binder. Recent studies of the environmental impact of CDI have pointed to the organic solvents used in the fabrication of CDI electrodes as key contributors to the overall environmental impact of the technology. Here, we report a scalable, aqueous processing approach to prepare MCDI electrodes using water-soluble polymer poly(vinyl alcohol) (PVA) as a binder and ion-exchange polymer. Electrodes are prepared by depositing aqueous slurry of activated carbon and PVA binder followed by coating with a thin layer of PVA-based cation- or anion-exchange polymer. When coated with ion-exchange layers, the PVA-bound electrodes exhibit salt adsorption capacities up to 14.4 mg/g and charge efficiencies up to 86.3%, higher than typically achieved for activated carbon electrodes with a hydrophobic polymer binder and ion-exchange membranes (5-13 mg/g). Furthermore, when paired with low-resistance commercial ion-exchange membranes, salt adsorption capacities exceed 18 mg/g. Our overall approach demonstrates a simple, environmentally friendly, cost-effective, and scalable method for the fabrication of high-capacity MCDI electrodes.

The importance of appropriate initial bacterial colonization of the intestine in newborn, child, and adult health.

The fetus does not reside in a sterile intrauterine environment and is exposed to commensal bacteria from the maternal gut/blood stream that cross the placenta and enter the amniotic fluid. This intestinal exposure to colonizing bacteria continues at birth and during the first year of life and has a profound influence on lifelong health. Why is this important? Intestinal crosstalk with colonizing bacteria in the developing intestine affects the infant's adaptation to extrauterine life (immune homeostasis) and provides protection against disease expression (allergy, autoimmune disease, obesity, etc.) later in life. Colonizing intestinal bacteria are critical to the normal development of host defense. Disrupted colonization (dysbiosis) due to maternal dysbiosis, cesarean section delivery, use of perinatal antibiotics, or premature delivery may adversely affect the gut development of host defense and predispose to inflammation rather than to homeostasis, leading to increased susceptibility to disease later in life. Babies born by cesarean section have a higher incidence of allergy, type 1 diabetes, and obesity. Infants given repeated antibiotic regimens during the first year of life are more likely to have asthma as adolescents. This research breakthrough helps to explain the shift in disease paradigms from infections to immune-mediated in children from developed countries. This review will develop this research breakthrough.

Secretions of Bifidobacterium infantis and Lactobacillus acidophilus Protect Intestinal Epithelial Barrier Function.

OBJECTIVES: The secreted metabolites of probiotics are cytoprotective to intestinal epithelium and have been shown to attenuate inflammation and reduce gut permeability. The present study was designed to determine the protective effects of probiotic conditioned media (PCM) from Bifidobacterium infantis (BCM) and Lactobacillus acidophilus (LCM) on interleukin (IL)-1ß-induced intestinal barrier compromise. METHODS: The epithelial barrier was determined by measuring the transepithelial electrical resistance (TER) across a Caco-2 cell monolayer using a Transwell model. The paracellular permeability was determined by fluorescein isothiocyanate-labeled dextran flux. The expression of tight junction (TJ) proteins and nuclear factor-kappa B (NF-κB) p65 were determined using Western blot and the distribution of NF-κB p65 was determined by immunofluorescence staining. RESULTS: BCM and LCM induced a dose-dependent increase in Caco-2 TER after 4 and 24 hours of incubation (P < 0.05). The maximal increase of Caco-2 TER occurred at 4 hours of treatment with a PCM concentration of 15%. Preincubation with BCM and LCM for 4 hours significantly prevented the decrease of Caco-2 TER induced by 24 hours of stimulation with 10 ng/mL IL-1ß. BCM and LCM decreased paracellular permeability in both stimulated and unstimulated Caco-2 monolayers (P < 0.05). IL-1ß stimulation decreased occludin expression and increased claudin-1 expression in Caco-2 cells (P < 0.05), which was prevented in cells treated with BCM or LCM. The changes of claudin-1 expression in H4 cells were similar to Caco-2 cells in response to PCM treatment and IL-1ß stimulation; however, a similar response in occludin was not demonstrated. The IL-1ß-induced nuclear translocation of NF-κB p65 in Caco-2 cells was prevented by pretreatment with both PCMs. CONCLUSIONS: BCM and LCM protected the intestinal barrier against IL-1ß stimulation by normalizing the protein expression of occludin and claudin-1 and preventing IL-1ß-induced NF-κB activation in Caco-2 cells, which may be partly responsible for the preservation of intestinal permeability.

Hydrocortisone-induced anti-inflammatory effects in immature human enterocytes depend on the timing of exposure.

The immature human gut has a propensity to exaggerated inflammatory responses that are thought to play a role in the pathogenesis of necrotizing enterocolitis (NEC). Prenatal exposure to corticosteroids has been reported to reduce the risk of NEC, while postnatal dexamethasone treatment is associated with adverse neurodevelopmental outcomes in preterm infants. The aim of this study was to investigate the direct role of hydrocortisone in gene expression patterns and inflammatory responses in immature human enterocytes. Time-dependent hydrocortisone effects in nontransformed primary human fetal intestinal epithelial cell line H4 were investigated by cDNA microarray. Fetal intestinal organ culture and cell culture experiments were conducted. Inflammatory responses were induced by stimulation with IL-1ß and TNF-α with and without hydrocortisone. IL-8 and IL-6 expression and secretion were measured as functional readout. Here we report time-dependent hydrocortisone-induced changes in gene expression patterns detected by cDNA microarray. Hydrocortisone significantly attenuated IL-1ß-induced inflammatory responses in the immature human gut when administered at the time of the proinflammatory insult: IL-1ß-induced IL-8 and IL-6 secretion in the fetal ileum as well as H4 cells were significantly reduced. Hydrocortisone also inhibited IL-8 secretion in response to TNF-α. In contrast, TNF-α-induced IL-8 secretion was not reduced in cells treated with hydrocortisone for 48 h before stimulation. Our observations provide a physiological basis for understanding the differential clinical effects of corticosteroids in the immature human gut depending on the timing of treatment.

Anti-inflammatory effects of Bifidobacterium longum subsp infantis secretions on fetal human enterocytes are mediated by TLR-4 receptors.

The therapeutic and preventive application of probiotics for necrotizing enterocolitis (NEC) has been supported by more and more experimental and clinical evidence in which Toll-like receptor 4 (TLR-4) exerts a significant role. In immune cells, probiotics not only regulate the expression of TLR-4 but also use the TLR-4 to modulate the immune response. Probiotics may also use the TLR-4 in immature enterocytes for anti-inflammation. Here we demonstrate that probiotic conditioned media (PCM) from Bifidobacterium longum supp infantis but not isolated organisms attenuates interleukin-6 (IL-6) induction in response to IL-1ß by using TLR-4 in a human fetal small intestinal epithelial cell line (H4 cells), human fetal small intestinal xenografts, mouse fetal small intestinal organ culture tissues, and primary NEC enterocytes. Furthermore, we show that PCM, using TLR-4, downregulates the mRNA expression of interleukin-1 receptor-associated kinase 2 (IRAK-2), a common adapter protein shared by IL-1ß and TLR-4 signaling. PCM also reduces the phosphorylation of the activator-protein 1 (AP-1) transcription factors c-Jun and c-Fos in response to IL-1ß stimulation in a TLR-4-dependent manner. This study suggests that PCM may use TLR-4 through IRAK-2 and via AP-1 to prevent IL-1ß-induced IL-6 induction in immature enterocytes. Based on these observations, the combined use of probiotics and anti-TLR-4 therapy to prevent NEC may not be a good strategy.

The Chronic Effects of Neurotrauma Consortium (CENC) multi-centre observational study: Description of study and characteristics of early participants.

PRIMARY OBJECTIVES: To establish and comprehensively evaluate a large cohort of US veterans who served in recent military conflicts in order to better understand possible chronic and late-life effects of mild traumatic brain injury (mTBI), including those that may stem from neurodegeneration. RESEARCH DESIGN: Cross-sectional and prospective longitudinal. METHODS AND PROCEDURES: Inclusion criteria are prior combat exposure and deployment(s) in Operation Enduring Freedom, Operation Iraqi Freedom or one of their follow-on conflicts (collectively OEF/OIF). Effects of mTBI will be assessed by enrolling participants across the entire spectrum of mTBI, from entirely negative to many mTBIs. Longitudinal assessments consist of in-person comprehensive testing at least every 5 years, with interval annual telephonic testing. The primary outcome is the composite score on the NIH Toolbox neuropsychological test battery. Assessments also include structured interviews, questionnaires, traditional neuropsychological testing, motor, sensory and vestibular functions, neuroimaging, electrophysiology, genotypes and biomarkers. MAIN OUTCOMES AND RESULTS: The authors fully describe the study methods and measures and report demographic and exposure characteristics from the early portion of the cohort of OEF/OIF veterans. CONCLUSIONS: This centrepiece observational study of the Chronic Effects of Neurotrauma Consortium (CENC) is successfully launched and, within several years, should provide fertile data to begin investigating its aims.

Testing the fading affect bias for healthy coping in the context of death.

Affect fades faster for unpleasant events than for pleasant events (e.g., Walker, Vogl, & Thompson, 1997 ), which is referred to as the fading affect bias (FAB; Walker, Skowronski, Gibbons, Vogl, & Thompson, 2003 ). Although research has generally shown that the FAB is a healthy coping mechanism, this same finding has not been demonstrated at a specific level of analysis accounting for particular event types and related individual differences (e.g., Gibbons et al., 2013 ). Given the strong unpleasant emotions associated with death (Rask, Kaunonen, & Paunonen-Ilmonen, 2002 ), the current study examined FAB in the context of death events and participant attitudes toward death. General healthy coping was shown by robust FAB across death and control (i.e., everyday) events and by a negative correlation between negative religious coping and FAB. Although healthy coping at a specific level of analysis was supported by increased FAB for participants who held accepting attitudes toward death when they recalled everyday events, it was not supported by decreased FAB for the same participants when they recalled death events. This effect was mediated by rehearsal ratings, not depression. Implications are discussed.

Mass balance and mass loading of polybrominated diphenyl ethers (PBDEs) in a tertiary wastewater treatment plant using SBSE-TD-GC/MS.

A mass loading and mass balance analysis was performed on selected polybromodiphenyl ethers (PBDEs) in the first full-scale indirect potable reuse treatment plant in the United States. Chemical analysis of PBDEs was performed using an environmentally friendly sample preparation technique, called stir-bar sorptive extraction (SBSE), coupled with thermal desorption and gas chromatography/mass spectrometry (GC/MS). The three most dominant PBDEs found in all the samples were: BDE-47, BDE-99 and BDE-100. In the wastewater influent, the concentrations of studied PBDEs ranged from 94 to 775 ng/L, and in the effluent, the levels were below the detection limit. Concentrations in sludge ranged from 50 to 182 ng/g. In general, a removal efficiency of 92-96% of the PBDEs in the plant was accomplished through primary and secondary processes. The tertiary treatment process was able to effectively reduce the aforementioned PBDEs to less than 10 ng/L (>96% removal efficiency) in the effluent. If PBDEs remain in the treated wastewater effluent, they may pose environmental and health impacts through aquifer recharge, irrigation, and sludge final disposal.

A Comparison of Water-Related Perceptions and Practices Among West Texas and South New Mexico Colonia Residents Using Hauled-Stored and Private Well Water.

In Texas, Arizona, and New Mexico, colonias refer to unincorporated rural settlements along the U.S.­Mexico border. Colonias lack governance and public services normally provided by local government (Ward, 1999). Residents typically rely on well water or hauled water stored in above-ground containers. This study attempted to quantify and compare water-related perceptions and practices of colonia residents. No significant differences were observed between colonia residents using well water versus hauled-stored water for water quality perceptions and water use practices. Most, however, had negative perceptions of their water supply; a majority perceived daily water supplies as not potable. Significant paradoxical discrepancies between perceptions and practice were identified. This study adds to a small but growing literature on subjective dimensions of quality of life indicators for colonia residents. Additional studies are needed to quantify the type and level of health risks posed by compromised water supplies for this vulnerable population. Understanding differences in perceptions and practices associated with water sources could help to identify which subpopulations of colonia residents are in greatest need of water infrastructure or remediation.

The very low birth weight infant microbiome and childhood health.

This review describes current understandings about the nature of the very low birth weight infant (VLBW) gut microbiome. VLBW infants often experience disruptive pregnancies and births, and prenatal factors can influence the maturity of the gut and immune system, and disturb microbial balance and succession. Many VLBWs experience rapid vaginal or Caesarean births. After birth these infants often have delays in enteral feeding, and many receive little or no mother's own milk. Furthermore the stressors of neonatal life in the hospital environment, common use of antibiotics, invasive procedures and maternal separation can contribute to dysbiosis. These infants experience gastrointestinal dysfunction, sepsis, transfusions, necrotizing enterocolitis, oxygen toxicity, and other pathophysiological conditions that affect the normal microbiota. The skin is susceptible to dysbiosis, due to its fragility and contact with NICU organisms. Dysbiosis in early life may resolve but little is known about the timing of the development of the signature gut microbiome in VLBWs. Dysbiosis has been associated with a number of physical and behavioral problems, including autism spectrum disorders, allergy and asthma, gastrointestinal disease, obesity, depression, and anxiety. Dysbiosis may be prevented or ameliorated in part by prenatal care, breast milk feeding, skin to skin contact, use of antibiotics only when necessary, and vigilance during infancy and early childhood.

Activation of epidermal growth factor receptor mediates mucin production stimulated by p40, a Lactobacillus rhamnosus GG-derived protein.

The mucus layer coating the gastrointestinal tract serves as the first line of intestinal defense against infection and injury. Probiotics promote mucin production by goblet cells in the intestine. p40, a Lactobacillus rhamnosus GG-derived soluble protein, has been shown to transactivate the EGF receptor (EGFR) in intestinal epithelial cells, which is required for inhibition of apoptosis and preservation of barrier function in the colon, thereby ameliorating intestinal injury and colitis. Because activation of EGFR has been shown to up-regulate mucin production in goblet cells, the purpose of this study was to investigate the effects and mechanisms of p40 regulation of mucin production. p40 activated EGFR and its downstream target, Akt, in a concentration-dependent manner in LS174T cells. p40 stimulated Muc2 gene expression and mucin production in LS174T cells, which were abolished by inhibition of EGFR kinase activity, down-regulation of EGFR expression by EGFR siRNA transfection, or suppression of Akt activation. Treatment with p40 increased mucin production in the colonic epithelium, thus thickening the mucus layer in the colon of wild type, but not of Egfr(wa5) mice, which have a dominant negative mutation in the EGFR kinase domain. Furthermore, inhibition of mucin-type O-linked glycosylation suppressed the effect of p40 on increasing mucin production and protecting intestinal epithelial cells from TNF-induced apoptosis in colon organ culture. Thus, these results suggest that p40-stimulated activation of EGFR mediates up-regulation of mucin production, which may contribute to the mechanisms by which p40 protects the intestinal epithelium from injury.

IL-17 mediates immunopathology in the absence of IL-10 following Leishmania major infection.

Leishmaniasis, resulting from infection with the protozoan parasite Leishmania, consists of a wide spectrum of clinical manifestations, from healing cutaneous lesions to fatal visceral infections. A particularly severe form of cutaneous leishmaniasis, termed mucosal leishmaniasis, exhibits decreased IL-10 levels and an exaggerated inflammatory response that perpetuates the disease. Using a mouse model of leishmaniasis, we investigated what cytokines contribute to increased pathology when IL-10-mediated regulation is absent. Leishmania major infected C57BL/6 mice lacking IL-10 regulation developed larger lesions than controls, but fewer parasites. Both IFN-γ and IL-17 levels were substantially elevated in mice lacking the capacity to respond to IL-10. IFN-γ promoted an increased infiltration of monocytes, while IL-17 contributed to an increase in neutrophils. Surprisingly, however, we found that IFN-γ did not contribute to increased pathology, but instead regulated the IL-17 response. Thus, blocking IFN-γ led to a significant increase in IL-17, neutrophils and disease. Similarly, the production of IL-17 by cells from leishmaniasis patients was also regulated by IL-10 and IFN-γ. Additional studies found that the IL-1 receptor was required for both the IL-17 response and increased pathology. Therefore, we propose that regulating IL-17, possibly by downregulating IL-1ß, may be a useful approach for controlling immunopathology in leishmaniasis.